5-Azacytidine, a cytidine analog, causes an induction of fetal hemoglobin synthesis in patients with thalassemia or sickle cell anemia. The mechanism of this effect is not yet clear. Two major hypotheses have dominated our experiments in this area: 1. that 5-azacytidine, in inducing genomic DNA hypomethylation, directly reactivates the gamma globin genes, and 2. that by disturbing the normal maturation of erythroid progenitor cells, the fetal program was somehow reactivated, allowing the progeny of these stem cells to produce more fetal hemoglobin. The available data suggest that the drug may act via a combination of hypomethylation and other "inductive" effects whose molecular mechanisms are not understood. Because of the potential carcinogenicity of this drug when administered chronically to humans, and the only moderate increase in HbF observed, we have discontinued human trials with 5-azacytidine. Our experiments regarding the mechanism of the drug are completed. For this reason, this project is being terminated.